Publications by authors named "Christopher Whitty"

140 Publications

The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis.

PLoS Med 2020 10 19;17(10):e1003359. Epub 2020 Oct 19.

MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom.

Background: Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as 'test-and-treat' policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM.

Methods And Findings: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify.

Conclusions: Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.
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http://dx.doi.org/10.1371/journal.pmed.1003359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571702PMC
October 2020

High Prevalence of among South Asian Migrants in Primary Care-Associations with Eosinophilia and Gastrointestinal Symptoms.

Pathogens 2020 Feb 6;9(2). Epub 2020 Feb 6.

Hospital for Tropical Diseases, University College London Hospitals, London WC1E 6JB, UK.

Gastrointestinal (GI) symptoms are a frequent reason for primary care consultation, and common amongst patients with strongyloidiasis. We conducted a prospective cohort and nested case control study in East London to examine the predictive value of a raised eosinophil count or of GI symptoms, for infection in South Asian migrants. We included 503 patients in the final analyses and all underwent a standardised GI symptom questionnaire, eosinophil count and serology testing. Positive serology was found in 33.6% in the eosinophilia cohort against 12.5% in the phlebotomy controls, with adjusted odds ratio of 3.54 (95% CI 1.88-6.67). In the GI symptoms cohort, 16.4% were seropositive but this was not significantly different compared with controls, nor were there associations between particular symptoms and Strongyloidiasis. Almost a third (35/115) of patients with a positive serology did not have eosinophilia at time of testing. Median eosinophil count declined post-treatment from 0.5 cells × 10/L (IQR 0.3-0.7) to 0.3 (0.1-0.5), < 0.001. We conclude infection is common in this setting, and the true symptom burden remains unclear. Availability of ivermectin in primary care would improve access to treatment. Further work should clarify cost-effectiveness of screening strategies for infection in UK migrant populations.
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http://dx.doi.org/10.3390/pathogens9020103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168230PMC
February 2020

Patients with positive malaria tests not given artemisinin-based combination therapies: a research synthesis describing under-prescription of antimalarial medicines in Africa.

BMC Med 2020 Jan 30;18(1):17. Epub 2020 Jan 30.

London School of Hygiene and Tropical Medicine, London, UK.

Background: There has been a successful push towards parasitological diagnosis of malaria in Africa, mainly with rapid diagnostic tests (mRDTs), which has reduced over-prescribing of artemisinin-based combination therapies (ACT) to malaria test-negative patients. The effect on prescribing for test-positive patients has received much less attention. Malaria infection in endemic Africa is often most dangerous for young children and those in low-transmission settings. This study examined non-prescription of antimalarials for patients with malaria infection demonstrated by positive mRDT results, and in particular these groups who are most vulnerable to poor outcomes if antimalarials are not given.

Methods: Analysis of data from 562,762 patients in 8 studies co-designed as part of the ACT Consortium, conducted 2007-2013 in children and adults, in Cameroon, Ghana, Nigeria, Tanzania, and Uganda, in a variety of public and private health care sector settings, and across a range of malaria endemic zones.

Results: Of 106,039 patients with positive mRDT results (median age 6 years), 7426 (7.0%) were not prescribed an ACT antimalarial. The proportion of mRDT-positive patients not prescribed ACT ranged across sites from 1.3 to 37.1%. For patients under age 5 years, 3473/44,539 (7.8%) were not prescribed an ACT, compared with 3833/60,043 (6.4%) of those aged ≥ 5 years. The proportion of < 5-year-olds not prescribed ACT ranged up to 41.8% across sites. The odds of not being prescribed an ACT were 2-32 times higher for patients in settings with lower-transmission intensity (using test positivity as a proxy) compared to areas of higher transmission. mRDT-positive children in low-transmission settings were especially likely not to be prescribed ACT, with proportions untreated up to 70%. Of the 7426 mRDT-positive patients not prescribed an ACT, 4121 (55.5%) were prescribed other, non-recommended non-ACT antimalarial medications, and the remainder (44.5%) were prescribed no antimalarial.

Conclusions: In eight studies of mRDT implementation in five African countries, substantial proportions of patients testing mRDT-positive were not prescribed an ACT antimalarial, and many were not prescribed an antimalarial at all. Patients most vulnerable to serious outcomes, children < 5 years and those in low-transmission settings, were most likely to not be prescribed antimalarials, and young children in low-transmission settings were least likely to be treated for malaria. This major public health risk must be addressed in training and practice.

Trial Registration: Reported in individual primary studies.
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http://dx.doi.org/10.1186/s12916-019-1483-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990477PMC
January 2020

UK vaccines network: Mapping priority pathogens of epidemic potential and vaccine pipeline developments.

Vaccine 2019 10 12;37(43):6241-6247. Epub 2019 Sep 12.

National Infection Service, Public Health England, Porton Down, Salisbury, Wiltshire SP4 0JG, UK. Electronic address:

During the 2013-2016 Ebola outbreak in West Africa an expert panel was established on the instructions of the UK Prime Minister to identify priority pathogens for outbreak diseases that had the potential to cause future epidemics. A total of 13 priority pathogens were identified, which led to the prioritisation of spending in emerging diseases vaccine research and development from the UK. This meeting report summarises the process used to develop the UK pathogen priority list, compares it to lists generated by other organisations (World Health Organisation, National Institutes of Allergy and Infectious Diseases) and summarises clinical progress towards the development of vaccines against priority diseases. There is clear technical progress towards the development of vaccines. However, the availability of these vaccines will be dependent on sustained funding for clinical trials and the preparation of clinically acceptable manufactured material during inter-epidemic periods.
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http://dx.doi.org/10.1016/j.vaccine.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127063PMC
October 2019

Clinical and Diagnostic Features of 413 Patients Treated for Imported Strongyloidiasis at the Hospital for Tropical Diseases, London.

Am J Trop Med Hyg 2019 08;101(2):428-431

Hospital for Tropical Diseases, University College Hospitals London NHS Foundation Trust, London, United Kingdom.

This study describes the clinical features of a cohort of imported cases of strongyloidiasis and the performance of standard diagnostic techniques for this condition. A total of 413 cases were identified, of whom 86 had microscopically proven infection. In proven cases, 23% had normal eosinophil counts, 19% had negative -specific serology, and 9.3% had normal blood counts and were seronegative. Serological testing was less sensitive for returning travelers (46.2%) than for migrants (89.7%). Immunosuppression, including human T-cell lymphotropic virus 1, was significantly associated with proven infection after controlling for age, presence of symptoms, duration of infection, and eosinophilia (OR 5.60, 95% CI 1.54-20.4). Patients with proven infection had lower serology values than those diagnosed with strongyloidiasis on the basis of positive serology and eosinophilia alone ( = 0.016). Symptomatic patients were significantly younger, had a shorter presumed duration of infection, and lower serology values. These data suggest a correlation between immunologic control of strongyloidiasis and the amplitude of the humoral response.
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http://dx.doi.org/10.4269/ajtmh.19-0087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685552PMC
August 2019

Malaria control stalls in high incidence areas.

BMJ 2019 05 21;365:l2216. Epub 2019 May 21.

Centre for Malaria Research, University of Health and Allied Sciences, Accra, Ghana.

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http://dx.doi.org/10.1136/bmj.l2216DOI Listing
May 2019

Imported malaria: key messages in an era of elimination.

Clin Med (Lond) 2019 03;19(2):153-156

Hospital for Tropical Diseases, London, UK.

Despite concerted efforts to eliminate malaria, it remains a major global cause of morbidity and mortality with over 200 million annual cases. Significant gains have been made, with the annual global malaria incidence and mortality halving over the past twenty years, using tools such as long-lasting insecticide-treated bed nets and artemisinin-based therapies. Malaria is also a significant cause of life-threatening imported infection in the UK. It is vital for front line clinical staff involved in the assessment of acutely ill patients to be aware of the need for early diagnostic testing, malaria epidemiology, markers of severe infection and developments in antimalarial treatments to optimise patient management. The difference between a good and poor outcome is early diagnosis and treatment. Many of the challenges faced in the quest for global eradication, such as availability of appropriate diagnostic tests, and drug and insecticide resistance could also have future implications for imported malaria.
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http://dx.doi.org/10.7861/clinmedicine.19-2-153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454370PMC
March 2019

Antimicrobial resistance: learning lessons from antiparasitic, antibacterial and antimycobacterial drug resistance in low-income settings.

Trans R Soc Trop Med Hyg 2019 03;113(3):105-107

Clinical Research Department, London School of Hygiene and Tropical Medicine, Keppel Street, London, UK.

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http://dx.doi.org/10.1093/trstmh/try146DOI Listing
March 2019

Geographical and temporal trends and seasonal relapse in Plasmodium ovale spp. and Plasmodium malariae infections imported to the UK between 1987 and 2015.

BMC Med 2018 11 27;16(1):218. Epub 2018 Nov 27.

Public Health England Malaria Reference Laboratory, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.

Background: Plasmodium ovale spp. and P. malariae cause illness in endemic regions and returning travellers. Far less is known about these species than P. falciparum and P. vivax.

Methods: The UK national surveillance data, collected 1987 to 2015, were collated with the International Passenger Survey and climatic data to determine geographical, temporal and seasonal trends of imported P. ovale spp. and P. malariae infection.

Results: Of 52,242 notified cases of malaria, 6.04% (3157) were caused by P. ovale spp. and 1.61% (841) by P. malariae; mortality was 0.03% (1) and 0.12% (1), respectively. Almost all travellers acquired infection in West or East Africa. Infection rate per travel episode fell fivefold during the study period. The median latency of P. malariae and P. ovale spp. was 18 and 76 days, respectively; delayed presentation occurred with both species. The latency of P. ovale spp. infection imported from West Africa was significantly shorter in those arriving in the UK during the West African peak malarial season compared to those arriving outside it (44 days vs 94 days, p < 0.0001), implying that relapse synchronises with the period of high malarial transmission. This trend was not seen in P. ovale spp. imported from East Africa nor in P. malariae.

Conclusion: In West Africa, where malaria transmission is highly seasonal, P. ovale spp. may have evolved to relapse during the malarial high transmission season. This has public health implications. Deaths are very rare, supporting current guidelines emphasising outpatient treatment. However, late presentations do occur.
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http://dx.doi.org/10.1186/s12916-018-1204-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260574PMC
November 2018

Building UK infrastructure for research that benefits infants, children and young people.

Arch Dis Child 2019 09 18;104(9):825-826. Epub 2018 Jul 18.

Department of Health and Social Care, National Institute for Health Research, London, UK.

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http://dx.doi.org/10.1136/archdischild-2017-314334DOI Listing
September 2019

Harveian Oration 2017: Triumphs and challenges in a world shaped by medicine.

Clin Med (Lond) 2017 12;17(6):537-544

Department of Health, UK; professor of public and international health, London School of Hygiene & Tropical Medicine

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http://dx.doi.org/10.7861/clinmedicine.17-6-537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297683PMC
December 2017

The changing aetiology of eosinophilia in migrants and returning travellers in the Hospital for Tropical Diseases, London 2002-2015: An observational study.

J Infect 2017 10 24;75(4):301-308. Epub 2017 Aug 24.

Infectious Diseases and Tropical Medicine, Hospital for Tropical Diseases, University College London Hospitals NHS Trust, UK. Electronic address:

Introduction: Determining the cause of eosinophilia in patients returning from the tropics continues to present a diagnostic challenge. The history, symptoms and degree of eosinophilia are often poor predictors of eventual diagnosis, but helminths are an important cause. The current British Infection Association recommendations use travel history to guide investigation of eosinophilia. However the global burden of helminth disease and travel patterns have changed over the last 3 decades and guidelines based on previous epidemiology need to be reviewed in the light of current data.

Methods: Consecutive patients presenting with, or referred for, investigation of eosinophilia were identified prospectively. Case notes, laboratory results and electronic records were reviewed for demographic and clinical data. Patients with an eosinophil count ≥0.50 × 10/L were included, and grouped based on lifetime history of travel to: West Africa, elsewhere in Africa, and the rest of the world. Results were compared to published data from 1997 to 2002 collected at the same centre.

Results: Of 410 patients who met the inclusion criteria, 407 had a documented travel history. Average yearly referrals for eosinophilia fell from 58 per year between 1997 and 2002, to 33 per year (2002-2015). The proportion of eosinophilia cases diagnosed with a parasitic cause fell from 64% to 50%, and yields for all parasitological investigations fell, the largest reduction in stool microscopy (20% yield to 9%) and day bloods for microfilariae (14% yield to 3%). Strongyloides stercoralis was the commonest diagnosis overall in our cohort, accounting for 50% of the total parasites diagnosed, and was present in 38% of patients from West Africa, 19% from rest of Africa, and 34% from rest of world; a relative increase compared to previous data. Schistosomiasis is slightly less common in those who had travelled to West Africa than the rest of Africa, and overall point prevalence has fallen from 33% (1997-2002) to 17% (2002-2015). Travellers were significantly less likely than patients who had immigrated to the UK to be diagnosed with any parasite (OR 0.54 95% CI 0.378-0.778 p = 0.0009).

Discussion: A parasitic cause will still be found in half of people returning from the tropics with an eosinophilia, but we observed a fall in the overall prevalence of parasitic diagnoses when compared with the earlier data. This may, in part, be explained by the impact of control programmes on the prevalence of parasites globally, especially filarial disease. S. stercoralis now represents the majority of parasites diagnosed in our cohort from all continents. We identified significantly higher rates of strongyloidiasis in immigrants than returning travellers. Despite the falling yields of stool microscopy and filarial serology the current guidelines based on travel history remain relevant with adequate yield.
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http://dx.doi.org/10.1016/j.jinf.2017.08.007DOI Listing
October 2017

Carbon Monoxide Poisoning: The Great Imitator.

Spartan Med Res J 2017 Aug 24;2(1):6343. Epub 2017 Aug 24.

Beaumont Hospital Southshore Campus, Trenton, MI. Michigan State University Department of Neurology & Ophthalmology, East Lansing MI.

Carbon Monoxide (CO) is one of the leading causes of poison deaths in the United States. Signs and symptoms are clinically variable secondary to inconsistent targeting of highly metabolic tissues by the gas. We report a case of a man in his early to mid-30's presenting to the emergency department with mental status changes, fatigue, headache, and flu-like symptoms for three days. The patient had been working on his motor vehicles in the garage during this time, using a portable diesel powered space heater to keep warm. Subsequent neurology and cardiology workup demonstrated bilateral globus pallidus (GP) lesions on brain imaging, increased non-myocardial infarction troponin levels, carboxyhemoglobin (COHb) level of 3.8%, elevated liver enzymes, and acute kidney failure. In this setting of his delayed presentation as a smoker with carbon monoxide poisoning, carboxyhemoglobin levels alone become less reliable. This report investigates the use of bilateral GP lesions, the most frequently affected structure, as well as damage preference to highly metabolic tissues to assist in diagnosis and prognosis for CO poisoning. Our observations can be used for further study of the relationship between bilateral GP necrosis and initial presentation and outcome of patients experiencing CO poisoning leading to earlier recognition, treatment, and decreased morbidity/mortality.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746039PMC
August 2017

The Impact of Introducing Malaria Rapid Diagnostic Tests on Fever Case Management: A Synthesis of Ten Studies from the ACT Consortium.

Am J Trop Med Hyg 2017 Oct 18;97(4):1170-1179. Epub 2017 Aug 18.

London School of Hygiene & Tropical Medicine, London, United Kingdom.

Since 2010, the World Health Organization has been recommending that all suspected cases of malaria be confirmed with parasite-based diagnosis before treatment. These guidelines represent a paradigm shift away from presumptive antimalarial treatment of fever. Malaria rapid diagnostic tests (mRDTs) are central to implementing this policy, intended to target artemisinin-based combination therapies (ACT) to patients with confirmed malaria and to improve management of patients with nonmalarial fevers. The ACT Consortium conducted ten linked studies, eight in sub-Saharan Africa and two in Afghanistan, to evaluate the impact of mRDT introduction on case management across settings that vary in malaria endemicity and healthcare provider type. This synthesis includes 562,368 outpatient encounters (study size range 2,400-432,513). mRDTs were associated with significantly lower ACT prescription (range 8-69% versus 20-100%). Prescribing did not always adhere to malaria test results; in several settings, ACTs were prescribed to more than 30% of test-negative patients or to fewer than 80% of test-positive patients. Either an antimalarial or an antibiotic was prescribed for more than 75% of patients across most settings; lower antimalarial prescription for malaria test-negative patients was partly offset by higher antibiotic prescription. Symptomatic management with antipyretics alone was prescribed for fewer than 25% of patients across all scenarios. In community health worker and private retailer settings, mRDTs increased referral of patients to other providers. This synthesis provides an overview of shifts in case management that may be expected with mRDT introduction and highlights areas of focus to improve design and implementation of future case management programs.
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http://dx.doi.org/10.4269/ajtmh.16-0955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637593PMC
October 2017

Use of malaria rapid diagnostic tests by community health workers in Afghanistan: cluster randomised trial.

BMC Med 2017 07 7;15(1):124. Epub 2017 Jul 7.

London School of Hygiene & Tropical Medicine, London, WC1H 7HT, UK.

Background: The World Health Organisation (WHO) recommends parasitological diagnosis of malaria before treatment, but use of malaria rapid diagnostic tests (mRDTs) by community health workers (CHWs) has not been fully tested within health services in south and central Asia. mRDTs could allow CHWs to diagnose malaria accurately, improving treatment of febrile illness.

Methods: A cluster randomised trial in community health services was undertaken in Afghanistan. The primary outcome was the proportion of suspected malaria cases correctly treated for polymerase chain reaction (PCR)-confirmed malaria and PCR negative cases receiving no antimalarial drugs measured at the level of the patient. CHWs from 22 clusters (clinics) received standard training on clinical diagnosis and treatment of malaria; 11 clusters randomised to the intervention arm received additional training and were provided with mRDTs. CHWs enrolled cases of suspected malaria, and the mRDT results and treatments were compared to blind-read PCR diagnosis.

Results: In total, 256 CHWs enrolled 2400 patients with 2154 (89.8%) evaluated. In the intervention arm, 75.3% (828/1099) were treated appropriately vs. 17.5% (185/1055) in the control arm (cluster adjusted risk ratio: 3.72, 95% confidence interval 2.40-5.77; p < 0.001). In the control arm, 85.9% (164/191) with confirmed Plasmodium vivax received chloroquine compared to 45.1% (70/155) in the intervention arm (p < 0.001). Overuse of chloroquine in the control arm resulted in 87.6% (813/928) of those with no malaria (PCR negative) being treated vs. 10.0% (95/947) in the intervention arm, p < 0.001. In the intervention arm, 71.4% (30/42) of patients with P. falciparum did not receive artemisinin-based combination therapy, partly because operational sensitivity of the RDTs was low (53.2%, 38.1-67.9). There was high concordance between recorded RDT result and CHW prescription decisions: 826/950 (87.0%) with a negative test were not prescribed an antimalarial. Co-trimoxazole was prescribed to 62.7% of malaria negative patients in the intervention arm and 15.0% in the control arm.

Conclusions: While introducing mRDT reduced overuse of antimalarials, this action came with risks that need to be considered before use at scale: an appreciable proportion of malaria cases will be missed by those using current mRDTs. Higher sensitivity tests could be used to detect all cases. Overtreatment with antimalarial drugs in the control arm was replaced with increased antibiotic prescription in the intervention arm, resulting in a probable overuse of antibiotics.

Trial Registration: ClinicalTrials.gov, NCT01403350 . Prospectively registered.
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http://dx.doi.org/10.1186/s12916-017-0891-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501368PMC
July 2017

Trend analysis of imported malaria in London; observational study 2000 to 2014.

Travel Med Infect Dis 2017 May - Jun;17:35-42. Epub 2017 Apr 26.

Field Epidemiology Services, South East and London, Public Health England, London, UK.

Background: We describe trends of malaria in London (2000-2014) in order to identify preventive opportunities and we estimated the cost of malaria admissions (2009/2010-2014/2015).

Methods: We identified all cases of malaria, resident in London, reported to the reference laboratory and obtained hospital admissions from Hospital Episode Statistics.

Results: The rate of malaria decreased (19.4[2001]-9.1[2014] per 100,000). Males were over-represented (62%). Cases in older age groups increased overtime. The rate was highest amongst people of Black African ethnicity followed by Indian, Pakistani, Bangladeshi ethnicities combined (103.3 and 5.5 per 100,000, respectively). The primary reason for travel was visiting friends and relatives (VFR) in their country of origin (69%), mostly sub-Saharan Africa (92%). The proportion of cases in VFRs increased (32%[2000]-50%[2014]) and those taking chemoprophylaxis decreased (36%[2000]-14%[2014]). The overall case fatality rate was 0.3%. We estimated the average healthcare cost of malaria admissions to be just over £1 million per year.

Conclusion: Our study highlighted that people of Black African ethnicity, travelling to sub-Saharan Africa to visit friends and relatives in their country of origin remain the most affected with also a decline in chemoprophylaxis use. Malaria awareness should focus on this group in order to have the biggest impact but may require new approaches.
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http://dx.doi.org/10.1016/j.tmaid.2017.04.004DOI Listing
October 2017

The contribution of biological, mathematical, clinical, engineering and social sciences to combatting the West African Ebola epidemic.

Philos Trans R Soc Lond B Biol Sci 2017 May;372(1721)

Clinical Research Department, London School of Hygiene and Tropical Medicine, Keppel Street, London SW1E 6NL, UK

The tragic West African Ebola epidemic claimed many lives, but would have been worse still if scientific insights from many disciplines had not been integrated to create a strong technical response. Epidemiology and modelling triggered the international response and guided where response efforts were directed; virology, engineering and clinical science helped reduce deaths and transmission in and from hospitals and treatment centres; social sciences were key to reducing deaths from funerals and in the community; diagnostic and operational research made the response more efficient; immunology and vaccine research contributed to the final stages of the epidemic and will help prevent future epidemics. These varied scientific contributions had to be integrated into a combined narrative, communicated to policymakers to inform decisions, and used by courageous local and international responders in the field in real time. Not every area of science was optimal, and in particular, clinical trials of simple interventions such as fluid management were slow to be adopted and sharing of data was initially poor. This Ebola epidemic demonstrated how science can respond to a major emergency, but also has lessons for better responses in future infectious emergencies.This article is part of the themed issue 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'.
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http://dx.doi.org/10.1098/rstb.2016.0293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394633PMC
May 2017

Impact of introduction of rapid diagnostic tests for malaria on antibiotic prescribing: analysis of observational and randomised studies in public and private healthcare settings.

BMJ 2017 Mar 29;356:j1054. Epub 2017 Mar 29.

London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.

 To examine the impact of use of rapid diagnostic tests for malaria on prescribing of antimicrobials, specifically antibiotics, for acute febrile illness in Africa and Asia. Analysisof nine preselected linked and codesigned observational and randomised studies (eight cluster or individually randomised trials and one observational study). Public and private healthcare settings, 2007-13, in Afghanistan, Cameroon, Ghana, Nigeria, Tanzania, and Uganda. 522 480 children and adults with acute febrile illness. Rapid diagnostic tests for malaria. Proportions of patients for whom an antibiotic was prescribed in trial groups who had undergone rapid diagnostic testing compared with controls and in patients with negative test results compared with patients with positive results. A secondary aim compared classes of antibiotics prescribed in different settings. Antibiotics were prescribed to 127 052/238 797 (53%) patients in control groups and 167 714/283 683 (59%) patients in intervention groups. Antibiotics were prescribed to 40% (35 505/89 719) of patients with a positive test result for malaria and to 69% (39 400/57 080) of those with a negative result. All but one study showed a trend toward more antibiotic prescribing in groups who underwent rapid diagnostic tests. Random effects meta-analysis of the trials showed that the overall risk of antibiotic prescription was 21% higher (95% confidence interval 7% to 36%) in intervention settings. In most intervention settings, patients with negative test results received more antibiotic prescriptions than patients with positive results for all the most commonly used classes: penicillins, trimethoprim-sulfamethoxazole (one exception), tetracyclines, and metronidazole. Introduction of rapid diagnostic tests for malaria to reduce unnecessary use of antimalarials-a beneficial public health outcome-could drive up untargeted use of antibiotics. That 69% of patients were prescribed antibiotics when test results were negative probably represents overprescription.This included antibiotics from several classes, including those like metronidazole that are seldom appropriate for febrile illness, across varied clinical, health system, and epidemiological settings. It is often assumed that better disease specific diagnostics will reduce antimicrobial overuse, but they might simply shift it from one antimicrobial class to another. Current global implementation of malaria testing might increase untargeted antibiotic use and must be examined.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370398PMC
http://dx.doi.org/10.1136/bmj.j1054DOI Listing
March 2017

Improving prescribing practices with rapid diagnostic tests (RDTs): synthesis of 10 studies to explore reasons for variation in malaria RDT uptake and adherence.

BMJ Open 2017 03 8;7(3):e012973. Epub 2017 Mar 8.

Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, UK.

Objectives: The overuse of antimalarial drugs is widespread. Effective methods to improve prescribing practice remain unclear. We evaluated the impact of 10 interventions that introduced rapid diagnostic tests for malaria (mRDTs) on the use of tests and adherence to results in different contexts.

Design: A comparative case study approach, analysing variation in outcomes across different settings.

Setting: Studies from the ACT Consortium evaluating mRDTs with a range of supporting interventions in 6 malaria endemic countries. Providers were governmental or non-governmental healthcare workers, private retail sector workers or community volunteers. Each study arm in a distinct setting was considered a case.

Participants: 28 cases from 10 studies were included, representing 148 461 patients seeking care for suspected malaria.

Interventions: The interventions included different mRDT training packages, supervision, supplies and community sensitisation.

Outcome Measures: Analysis explored variation in: (1) uptake of mRDTs (% febrile patients tested); (2) provider adherence to positive mRDTs (% positive prescribed/given Artemisinin Combination Treatment); (3) provider adherence to negative mRDTs (% negative not prescribed/given antimalarial).

Results: Outcomes varied widely across cases: 12-100% mRDT uptake; 44-98% adherence to positive mRDTs; 27-100% adherence to negative mRDTs. Providers appeared more motivated to perform well when mRDTs and intervention characteristics fitted with their own priorities. Goodness of fit of mRDTs with existing consultation and diagnostic practices appeared crucial to maximising the impact of mRDTs on care, as did prior familiarity with malaria testing; adequate human resources and supplies; possible alternative treatments for mRDT-negative patients; a more directive intervention approach and local preferences for ACTs.

Conclusions: Basic training and resources are essential but insufficient to maximise the potential of mRDTs in many contexts. Programme design should respond to assessments of provider priorities, expectations and capacities. As mRDTs become established, the intensity of supporting interventions required seems likely to reduce.
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http://dx.doi.org/10.1136/bmjopen-2016-012973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353269PMC
March 2017

Introducing malaria rapid diagnostic tests in private medicine retail outlets: A systematic literature review.

PLoS One 2017 2;12(3):e0173093. Epub 2017 Mar 2.

Department of Global Health and Development, London School of Hygiene & Tropical Medicine, London, United Kingdom.

Background: Many patients with malaria-like symptoms seek treatment in private medicine retail outlets (PMR) that distribute malaria medicines but do not traditionally provide diagnostic services, potentially leading to overtreatment with antimalarial drugs. To achieve universal access to prompt parasite-based diagnosis, many malaria-endemic countries are considering scaling up malaria rapid diagnostic tests (RDTs) in these outlets, an intervention that may require legislative changes and major investments in supporting programs and infrastructures. This review identifies studies that introduced malaria RDTs in PMRs and examines study outcomes and success factors to inform scale up decisions.

Methods: Published and unpublished studies that introduced malaria RDTs in PMRs were systematically identified and reviewed. Literature published before November 2016 was searched in six electronic databases, and unpublished studies were identified through personal contacts and stakeholder meetings. Outcomes were extracted from publications or provided by principal investigators.

Results: Six published and six unpublished studies were found. Most studies took place in sub-Saharan Africa and were small-scale pilots of RDT introduction in drug shops or pharmacies. None of the studies assessed large-scale implementation in PMRs. RDT uptake varied widely from 8%-100%. Provision of artemisinin-based combination therapy (ACT) for patients testing positive ranged from 30%-99%, and was more than 85% in five studies. Of those testing negative, provision of antimalarials varied from 2%-83% and was less than 20% in eight studies. Longer provider training, lower RDT retail prices and frequent supervision appeared to have a positive effect on RDT uptake and provider adherence to test results. Performance of RDTs by PMR vendors was generally good, but disposal of medical waste and referral of patients to public facilities were common challenges.

Conclusions: Expanding services of PMRs to include malaria diagnostic services may hold great promise to improve malaria case management and curb overtreatment with antimalarials. However, doing so will require careful planning, investment and additional research to develop and sustain effective training, supervision, waste-management, referral and surveillance programs beyond the public sector.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173093PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333947PMC
September 2017

Changes in the availability and affordability of subsidised artemisinin combination therapy in the private drug retail sector in rural Ghana: before and after the introduction of the AMFm subsidy.

Int Health 2016 11 15;8(6):427-432. Epub 2016 Oct 15.

Dodowa Health Research Center, Ghana Health Service, P.O. Box DD1, Dodowa, Ghana.

Background: Most people with febrile illness are treated in the private drug retail sector. Ghana was among nine countries piloting the Global Fund Affordable Medicines Facility - malaria (AMFm). AMFm aimed to: increase artemisinin combination therapy (ACT) affordability; increase ACT availability; increase ACT use; and 'crowd out' artemisinin monotherapies.

Methods: Three censuses were carried out 2 months before (2010), 2 months after and 2.5 years after (2013) the first co-paid ACTs to assess changes in antimalarial (AM) availability and price in private retail shops in a Ghanaian rural district to assess the sustainability of the initial gains. Supply, stock-out and cost were explored.

Results: Of 62 shops in the district, 56 participated with 398, 388 and 442 brands of AMs in the shops during the 3 censuses. The proportion of ACTs increased over the period while monotherapies reduced. Herbal-based AM preparations comprised 40-45% of AMs in stock with minimal variation over the period. ACTs were the most sold AM type for all ages but overall buying and selling prices of Quality Assured-ACTs increased by 40-100%.

Conclusions: Initial gains in ACT availability were sustained, but not improved on 2.5 years after AMFm. Widespread availability of unproven herbal medicines is a concern; AMFm had little impact on this.
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http://dx.doi.org/10.1093/inthealth/ihw041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181550PMC
November 2016

Examining Intervention Design: Lessons from the Development of Eight Related Malaria Health Care Intervention Studies.

Health Syst Reform 2016 Oct 15;2(4):373-388. Epub 2016 Sep 15.

Disease Control Department , London School of Hygiene & Tropical Medicine , London , UK.

-Rigorous evidence of "what works" to improve health care is in demand, but methods for the development of interventions have not been scrutinized in the same ways as methods for evaluation. This article presents and examines intervention development processes of eight malaria health care interventions in East and West Africa. A case study approach was used to draw out experiences and insights from multidisciplinary teams who undertook to design and evaluate these studies. Four steps appeared necessary for intervention design: (1) definition of scope, with reference to evaluation possibilities; (2) research to inform design, including evidence and theory reviews and empirical formative research; (3) intervention design, including consideration and selection of approaches and development of activities and materials; and (4) refining and finalizing the intervention, incorporating piloting and pretesting. Alongside these steps, projects produced theories, explicitly or implicitly, about (1) intended pathways of change and (2) how their intervention would be implemented.The work required to design interventions that meet and contribute to current standards of evidence should not be underestimated. Furthermore, the process should be recognized not only as technical but as the result of micro and macro social, political, and economic contexts, which should be acknowledged and documented in order to infer generalizability. Reporting of interventions should go beyond descriptions of final intervention components or techniques to encompass the development process. The role that evaluation possibilities play in intervention design should be brought to the fore in debates over health care improvement.
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http://dx.doi.org/10.1080/23288604.2016.1179086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176770PMC
October 2016

Geographical and temporal trends in imported infections from the tropics requiring inpatient care at the Hospital for Tropical Diseases, London - a 15 year study.

Trans R Soc Trop Med Hyg 2016 08 12;110(8):456-63. Epub 2016 Sep 12.

Hospital for Tropical Diseases, London, UK.

Background: Understanding geographic and temporal trends in imported infections is key to the management of unwell travellers. Many tropical infections can be managed as outpatients, with admission reserved for severe cases.

Methods: We prospectively recorded the diagnosis and travel history of patients admitted between 2000 and 2015. We describe the common tropical and non-tropical infectious diseases and how these varied based on region, reason for travel and over time.

Results: A total of 4362 admissions followed an episode of travel. Falciparum malaria was the most common diagnosis (n=1089). Among individuals who travelled to Africa 1206/1724 (70.0%) had a tropical diagnosis. The risk of a tropical infection was higher among travellers visiting friends and relatives than holidaymakers (OR 2.8, p<0.001). Among travellers to Asia non-tropical infections were more common than tropical infections (349/782, 44.6%), but enteric fever (117, 33.5%) of the tropical infections and dengue (70, 20.1%) remained important. The number of patients admitted with falciparum malaria declined over the study but those of enteric fever and dengue did not.

Conclusions: Most of those arriving from sub-Saharan Africa with an illness requiring admission have a classical tropical infection, and malaria still predominates. In contrast, fewer patients who travelled to Asia have a tropical diagnosis but enteric fever and dengue remain relatively common. Those visiting friends and relatives are most likely to have a tropical infection.
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http://dx.doi.org/10.1093/trstmh/trw053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034884PMC
August 2016

Factors influencing choice of care-seeking for acute fever comparing private chemical shops with health centres and hospitals in Ghana: a study using case-control methodology.

Malar J 2016 05 25;15(1):290. Epub 2016 May 25.

London School of Hygiene & Tropical Medicine, London, UK.

Background: Several public health interventions to improve management of patients with fever are largely focused on the public sector yet a high proportion of patients seek care outside the formal healthcare sector. Few studies have provided information on the determinants of utilization of the private sector as against formal public sector. Understanding the differences between those who attend public and private health institutions, and their pathway to care, has significant practical implications. The chemical shop is an important source of care for acute fever in Ghana.

Methods: Case-control methodology was used to identify factors associated with seeking care for fever in the Dangme West District, Ghana. People presenting to health centres, or hospital outpatients, with a history or current fever were compared to counterparts from the same community with fever visiting a chemical shop.

Results: Of 600 patients, 150 each, were recruited from the district hospital and two health centres, respectively, and 300 controls from 51 chemical shops. Overall, 103 (17.2 %) patients tested slide positive for malaria. Specifically, 13.7 % (41/300) of chemical shop patients, 30.7 % (46/150) health centre and 10.7 % (16/150) hospital patients were slide positive. While it was the first option for care for 92.7 % (278/300) chemical shop patients, 42.7 % (64/150) of health centre patients first sought care from a chemical shop. More health centre patients (61.3 %; 92/150) presented with fever after more than 3 days than chemical shop patients (27.7 %; 83/300) [AOR = 0.19; p < 0.001 CI 0.11-0.30]. Although the hospital was the first option for 83.3 % (125/150) of hospital patients, most (63.3 %; 95/150) patients arrived there over 3 days after their symptoms begun. Proximity was significantly associated with utilization of each source of care. Education, but not other socioeconomic or demographic factors were significantly associated with chemical shop use.

Conclusions: The private drug retail sector is the first option for the majority of patients, including poorer patients, with fever in this setting. Most patients with fever arrive at chemical shops with less delay and fewer signs of severity than at public health facilities. Improving chemical shop skills is a good opportunity to diagnose, treat or refer people with fever early.
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http://dx.doi.org/10.1186/s12936-016-1351-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880965PMC
May 2016

UK malaria treatment guidelines 2016.

J Infect 2016 06 12;72(6):635-649. Epub 2016 Feb 12.

Malaria Reference Laboratory, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.

1.Malaria is the tropical disease most commonly imported into the UK, with 1300-1800 cases reported each year, and 2-11 deaths. 2. Approximately three quarters of reported malaria cases in the UK are caused by Plasmodium falciparum, which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. 3. Most non-falciparum malaria cases are caused by Plasmodium vivax; a few cases are caused by the other species of plasmodium: Plasmodium ovale, Plasmodium malariae or Plasmodium knowlesi. 4. Mixed infections with more than one species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria. 5. There are no typical clinical features of malaria; even fever is not invariably present. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints. 6. A diagnosis of malaria must always be sought in a feverish or sick child or adult who has visited malaria-endemic areas. Specific country information on malaria can be found at http://travelhealthpro.org.uk/. P. falciparum infection rarely presents more than six months after exposure but presentation of other species can occur more than a year after exposure. 7. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until more than one blood specimen has been examined. Other travel related infections, especially viral haemorrhagic fevers, should also be considered. 8. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites. P. falciparum and P. vivax (depending upon the product) malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens. RDTs for other Plasmodium species are not as reliable. 9. Most patients treated for P. falciparum malaria should be admitted to hospital for at least 24 h as patients can deteriorate suddenly, especially early in the course of treatment. In specialised units seeing large numbers of patients, outpatient treatment may be considered if specific protocols for patient selection and follow up are in place. 10. Uncomplicated P. falciparum malaria should be treated with an artemisinin combination therapy (Grade 1A). Artemether-lumefantrine (Riamet(®)) is the drug of choice (Grade 2C) and dihydroartemisinin-piperaquine (Eurartesim(®)) is an alternative. Quinine or atovaquone-proguanil (Malarone(®)) can be used if an ACT is not available. Quinine is highly effective but poorly-tolerated in prolonged treatment and should be used in combination with an additional drug, usually oral doxycycline. 11. Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized) should be treated with intravenous therapy until the patient is well enough to continue with oral treatment. Severe malaria is a rare complication of P. vivax or P. knowlesi infection and also requires parenteral therapy. 12. The treatment of choice for severe or complicated malaria in adults and children is intravenous artesunate (Grade 1A). Intravenous artesunate is unlicensed in the EU but is available in many centres. The alternative is intravenous quinine, which should be started immediately if artesunate is not available (Grade 1A). Patients treated with intravenous quinine require careful monitoring for hypoglycemia. 13. Patients with severe or complicated malaria should be managed in a high-dependency or intensive care environment. They may require haemodynamic support and management of: acute respiratory distress syndrome, disseminated intravascular coagulation, acute kidney injury, seizures, and severe intercurrent infections including Gram-negative bacteraemia/septicaemia. 14. Children with severe malaria should also be treated with empirical broad spectrum antibiotics until bacterial infection can be excluded (Grade 1B). 15. Haemolysis occurs in approximately 10-15% patients following intravenous artesunate treatment. Haemoglobin concentrations should be checked approximately 14 days following treatment in those treated with IV artemisinins (Grade 2C). 16. Falciparum malaria in pregnancy is more likely to be complicated: the placenta contains high levels of parasites, stillbirth or early delivery may occur and diagnosis can be difficult if parasites are concentrated in the placenta and scanty in the blood. 17. Uncomplicated falciparum malaria in the second and third trimester of pregnancy should be treated with artemether-lumefantrine (Grade 2B). Uncomplicated falciparum malaria in the first trimester of pregnancy should usually be treated with quinine and clindamycin but specialist advice should be sought. Severe malaria in any trimester of pregnancy should be treated as for any other patient with artesunate preferred over quinine (Grade 1C). 18. Children with uncomplicated malaria should be treated with an ACT (artemether-lumefantrine or dihydroartemisinin-piperaquine) as first line treatment (Grade 1A). Quinine with doxycycline or clindamycin, or atovaquone-proguanil at appropriate doses for weight can also be used. Doxycycline should not be given to children under 12 years. 19. Either an oral ACT or chloroquine can be used for the treatment of non-falciparum malaria. An oral ACT is preferred for a mixed infection, if there is uncertainty about the infecting species, or for P. vivax infection from areas where chloroquine resistance is common (Grade 1B). 20. Dormant parasites (hypnozoites) persist in the liver after treatment of P. vivax or P. ovale infection: the only currently effective drug for eradication of hypnozoites is primaquine (1A). Primaquine is more effective at preventing relapse if taken at the same time as chloroquine (Grade 1C). 21. Primaquine should be avoided or given with caution under expert supervision in patients with Glucose-6-phosphate dehydrogenase deficiency (G6PD), in whom it may cause severe haemolysis. 22. Primaquine (for eradication of P. vivax or P. ovale hypnozoites) is contraindicated in pregnancy and when breastfeeding (until the G6PD status of child is known); after initial treatment for these infections a pregnant woman should take weekly chloroquine prophylaxis until after delivery or cessation of breastfeeding when hypnozoite eradication can be considered. 23. An acute attack of malaria does not confer protection from future attacks: individuals who have had malaria should take effective anti-mosquito precautions and chemoprophylaxis during future visits to endemic areas.
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http://dx.doi.org/10.1016/j.jinf.2016.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132403PMC
June 2016